Single-cell and genome-wide Mendelian randomization identifies causative genes for gout

Abstract

Background: Gout is a prevalent manifestation of metabolic osteoarthritis induced by elevated blood uric acid levels. The purpose of this study was to investigate the mechanisms of gene expression regulation in gout disease and elucidate its pathogenesis.

Methods: The study integrated gout genome-wide association study (GWAS) data, single-cell transcriptomics (scRNA-seq), expression quantitative trait loci (eQTL), and methylation quantitative trait loci (mQTL) data for analysis, and utilized two-sample Mendelian randomization study to comprehend the causal relationship between proteins and gout.

Results: We identified 17 association signals for gout at unique genetic loci, including four genes related by protein-protein interaction network (PPI) analysis: TRIM46, THBS3, MTX1, and KRTCAP2. Additionally, we discerned 22 methylation sites in relation to gout. The study also found that genes such as TRIM46, MAP3K11, KRTCAP2, and TM7SF2 could potentially elevate the risk of gout. Through a Mendelian randomization (MR) analysis, we identified three proteins causally associated with gout: ADH1B, BMP1, and HIST1H3A.

Conclusion: According to our findings, gout is linked with the expression and function of particular genes and proteins. These genes and proteins have the potential to function as novel diagnostic and therapeutic targets for gout. These discoveries shed new light on the pathological mechanisms of gout and clear the way for future research on this condition.

Keywords: GWAS; Gout; Mendelian randomization; Summary-data-based Mendelian randomization; scRNA-seq.

Fig. 1

Flowchart of the analyses performed

Fig. 2

The outcomes of Mendelian randomization, showcasing the relationship between expression quantitative trait loci and the risk of gout, are presented. b_SMR is a marker for the magnitude of effect (β) of the gene variant on the expression of genes. A positive relationship is indicated when β is greater than zero, whereas β less than zero implies a negative relationship. OR, representing odd ratios, is determined from the projection of the causal estimate (β coefficient). The confidence interval, represented by 95%CI, is calculated utilizing β and standard error (SE)

Fig. 3

The findings of Mendelian randomization, establishing a connection between methylation quantitative trait loci and the danger of gout, are illustrated. b_SMR symbolizes the impact magnitude (β) of the variant location on DNA methylation. When β is greater than zero, it signifies a positive association, and conversely, β less than zero signifies a negative association. OR, signifying odd ratios, is derived from the forecasted causal estimate (β coefficients). The term 95%CI represents confidence boundaries, ascertained using β and standard error (SE)

Fig. 4

The outcomes from Mendelian randomization, illustrating the correlation between methylation quantitative trait loci and expression quantitative trait loci, are reported. The influence magnitude (β) of a DNA methylation variant location on gene expression is indicated by SMR. A positive association is suggested when β is greater than zero, while a negative association is implied when β is less than zero. OR, the acronym for odd ratios, is computed based on the projected causal estimate (β coefficients). The term 95%CI signifies confidence ranges, which are derived using β and standard error (SE)

Fig. 5

Multifaceted connections between DNA Methylation and gene expression

Fig. 6

Single-cell sequencing analysis